Antiestrogen Combination Improves Breast Cancer Survival
August 2, 2012 — The combination of anastrozole (Arimidex, AstraZeneca) plus fulvestrant (Faslodex) is better than anastrozole alone for delaying disease progression and improving survival in postmenopausal women with hormone-receptor-positive metastatic breast cancer.
The data are published in the August 2 issue of the New England Journal of Medicine.
A study led by Rita Mehta, MD, associate health science professor of medicine at the University of California, Irvine, showed that median progression-free survival, the primary end point, improved significantly, from 13.5 months with anastrozole alone to 15.0 months with the combination (P = .007).
In addition, median overall survival, the secondary end point, improved significantly, from 41.3 months with anastrozole alone to 47.7 months with the combination (hazard ratio [HR] for death, 0.81; 95% confidence interval, 0.65 to 1.00; P = .05). This 6-month difference occurred despite the fact that 41% of patients treated with anastrozole alone crossed over to fulvestrant alone after progression.
Change Standard of Care?
The results of this trial were initially presented at the 2011 San Antonio Breast Cancer Symposium, and were reported at that time by Medscape Medical News.
"This will likely change the standard of care," coauthor Kathy Albain, MD, from Loyola University Medical Center in Chicago, Illinois, said at the time.
When the results were first presented, Dr. Mehta noted that "these patients have not had a new treatment that gave them an overall survival benefit" in more than a decade.
The use of this combination is not new. At the symposium, C. Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine in Houston, Texas, told Medscape Medical News that he combines "the 2 at progression to an aromatase inhibitor because studies have shown that [fulvestrant] works best in a low-estrogen environment."
Kathy Miller, MD, from Indiana University Melvin and Bren Simon Cancer Center in Indianapolis, also uses this regimen. "I have used the combined regimen in the population most commonly enrolled in this trial and the subset where there is/was the greatest benefit; namely, those who presented with metastatic disease or who had not received previous adjuvant tamoxifen. I agree…that the results warrant a trial in the adjuvant setting," said Dr. Miller, who writes the Miller on Oncology blog for Medscape Medical News.
Previous Trials Negative
Dr. Mehta and colleagues note that their results conflict with those from the Fulvestrant and Anastrozole Combination Therapy (FACT) trial (J Clin Oncol. 2012;30:1919-1925).
In FACT, anastrozole plus fulvestrant was not superior to anastrozole alone. However, there were fewer patients in the FACT trial, and there were patients with locally recurrent disease, which is associated with fewer failure events.
A larger study would have been required to detect a difference between the groups, Dr. Mehta and colleagues point out. In addition, the FACT cohort involved women who experienced progressive disease while receiving adjuvant chemotherapy, and all patients were in relapse after the treatment of local disease.
Most previous studies have failed to show that a combination of agents is superior to monotherapy, particularly for overall survival, Dr. Mehta and colleagues report. "Indeed, in the adjuvant setting, the combination of anastrozole with tamoxifen is inferior to anastrozole alone," they note.
Improvement Increases Over Time
In the trial conducted by Dr. Mehta's team, 707 postmenopausal women with hormone-receptor-positive metastatic breast cancer were randomized, from 2004 to 2009, to sequential or combination therapy. Women received either oral anastrozole 1 mg daily (crossover to fulvestrant alone was strongly encouraged if disease progressed) or oral anastrozole 1 mg daily plus intramuscular fulvestrant (500 mg on day 1, 250 mg on days 14 and 28, and monthly thereafter).
Overall, the combination was more effective than anastrozole alone in all subgroups, and there were no significant interactions, the authors report.
A total of 565 events (progression or death) were observed for the primary analysis — 297 with anastrozole alone and 268 with the combination. As of September 29, 2011, the median follow-up time for progression-free survival in patients without an event was 35 months (range, 3 to 78).
For progression-free survival, the superiority of the combination emerged over time. At 1 year, the rate was 57% for the combination and 56% for anastrozole alone; at 2 years, the rates were 35% and 28%, respectively; at 3 years, the rates were 25% and 16%.
There were 176 deaths with anastrozole alone and 154 with the combination. As with progression-free survival, the difference in overall survival between the 2 groups increased over time. At 1 year, the rate of was 89% with anastrozole alone and 91% with the combination; at 2 years, that rate had widened to 75% and 79%, respectively; at 3 years, it was 57% and 62%.
The estimated HR for death with the combination was 0.81.
Both regimens were associated with mild to moderate toxic effects, the authors report. Although grade 3 to 5 toxic effects occurred more frequently with the combination than with anastrozole alone, the between-group difference was not significant, they note.
Previous Tamoxifen Therapy
The authors analyzed the data according to whether or not women had received previous treatment with tamoxifen.
For the 414 women (59.7%) who had not received previous tamoxifen therapy, both progression-free survival and overall survival were significantly better with the combination than with anastrozole alone. For these women, median progression-free survival was 12.6 months with anastrozole alone and 17.0 months with the combination (HR, 0.74; P = .006). Overall survival was also significantly different (HR, 0.74; P = .04).
However, for women who had previously received tamoxifen therapy, neither progression-free survival nor overall survival was significantly better with the combination. In these women, median progression-free survival was 14.1 months with anastrozole alone and 13.5 months with the combination (HR, 0.89; P = .37).
The study was funded by the National Cancer Institute and AstraZeneca.